Non-inferiority RCT: Reduced-Dose vs Full-Dose Direct Oral Anticoagulants for Extended VTE Treatment

Background: Venous thromboembolism (VTE) carries a high risk of recurrence once anticoagulation is stopped, particularly in those with unprovoked events or persistent risk factors. Extended anticoagulation is therefore recommended for patients at high risk, but optimal dosing remains uncertain. Reduced-dose direct oral anticoagulants (DOACs) may lower bleeding risk compared with full-dose regimens. However, prior trials that tested reduced-dose anticoagulation enrolled patients with less definitive indications for continuation and were not powered for head-to-head efficacy comparisons.

Objective: The RENOVE trial aimed to determine whether reduced-dose DOACs (apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily) are non-inferior to full-dose DOACs (apixaban 5 mg twice daily or rivaroxaban 20 mg once daily) in preventing VTE recurrence during extended treatment, while potentially reducing bleeding risk.

Methods: RENOVE was a non-inferiority, multicenter, randomized, open-label, blinded-endpoint trial conducted in 47 French hospitals. It included adult patients (n=2768) who had completed 6–24 months of uninterrupted full-dose anticoagulation for symptomatic pulmonary embolism or proximal deep vein thrombosis and were deemed at high risk for recurrence. Participants were randomly assigned 1:1 to a reduced-dose or a full-dose DOAC regimen. The primary outcome was symptomatic recurrent VTE (non-fatal or fatal). The main secondary outcomes included major bleeding or clinically relevant non-major bleeding, and a net clinical benefit composite of recurrent VTE plus major or clinically relevant non-major bleeding.

Results: After a median follow-up of 37.1 months, the primary outcome occurred in 19/1383 patients (5-year cumulative incidence 2.2%) in the reduced-dose arm and 15/1385 (1.8%) in the full-dose arm (adjusted HR 1.32; 95% CI 0.67–2.60; p=0.23 for non-inferiority). Major or clinically relevant non-major bleeding was significantly lower in the reduced-dose group (9.9% vs 15.2% at 5 years; HR 0.61; 95% CI 0.48–0.79). Major bleeding was 2.1% vs 4.0%, respectively. Net clinical benefit (recurrent VTE or clinically relevant bleeding) was 11.8% in the reduced-dose group versus 16.5% in the full-dose group (HR 0.67; 95% CI 0.53–0.86). Mortality and arterial events were similar between groups.

Conclusions: Reduced-dose DOACs did not meet the formal non-inferiority criterion for preventing VTE recurrence in patients requiring extended anticoagulation. Nonetheless, absolute recurrence rates were low in both arms. The reduced-dose strategy substantially lowered the risk of clinically relevant bleeding without increasing all-cause mortality. Although full-dose anticoagulation remains an option, these findings suggest that reduced-dose regimens may be clinically reasonable for many patients who need ongoing therapy.

Implications for Practice: Clinicians could consider a reduced-dose DOAC regimen for extended VTE treatment, especially in individuals at high bleeding risk, given the observed safety benefits. Treatment decisions should still account for patient-specific factors (e.g., obesity, history of severe VTE) where full-dose regimens might remain preferable.

Study Strengths and Limitations: Major strengths include the large sample size, well-defined endpoints adjudicated by a blinded committee, and extended follow-up. Limitations include the open-label design and the low rate of recurrence, which led to a sample size increase mid-study. Subgroup analyses may be underpowered to detect meaningful differences in specific populations.

Future Research: Further trials or pooled analyses are needed to clarify whether certain high-risk subgroups (e.g., those with severe obesity or active malignancy) might benefit more from continuing a full-dose regimen. Additional prospective studies could refine criteria for safe dose reductions.

Reference:

1. Couturaud F, Schmidt J, Sanchez O, et al. Extended treatment of venous thromboembolism with reduced-dose versus full-dose direct oral anticoagulants in patients at high risk of recurrence: a non-inferiority, multicentre, randomised, open-label, blinded endpoint trial. The Lancet. 2025;405(10480). DOI: https://doi.org/10.1016/S0140-6736(24)02842-3
2. Middeldorp S, Leentjens J. Anticoagulation for extended venous thromboembolism treatment: less is really more. The Lancet. 2025;405(10480). DOI: https://doi.org/10.1016/S0140-6736(25)00099-6